Osteogenesis, a phenomenon of bone regeneration by osteoblasts, is important in maintaining vertebrate organisms. Many factors involved in osteogenesis are known, such as hormones, such as estrogen, calcitonine and parathyroid hormone (PHT), growth factors, such as osteogenetic factor (BMP: Bone Morphogenetic Protein), and medicines, such as activated vitamin D, a calcium drug, and vitamin K. BMP, a group of diffusible factors belonging to the TGF-β family, has been reported to include about 20 kinds of genes (Molecular Medicine, 37, 634 (2000)). Among them, BMP-2 and BMP-4 have been reported by many to possess a modulatory activity of bone differentiation. On the other hand, BMP, expected as a novel remedy for bone-related diseases, is the only cytokine possessing an activity as a signal of ectopic formation. BMP is thought to be useful for osteogenesis (endochondral ossification), which takes place in a repair reaction at a bone fracture or a bone defect, and which is caused by displacement of chondroid by neonatal bone (Developmental Biology, 174, 448 (1996). Journal of Bone and Mineral Research, 9(5), 651 (1994)). It has also been reported that mesenchymal stem cells have pluripotency and can differentiate to adipocytes, cartilage cells or osteoblasts, depending on the culture condition (Science, 284, 143 (1999)) and that the bone differentiation of mesenchymal stem cells is induced by BMP-2 (Journal of Cell Biology, 113, 681 (1991)). Thus, BMP, which induces bone differentiation, is thought to be associated with osteogenesis-related diseases, such as rheumatoid arthritis, osteoarthritis or osteoporosis. Actually, gene therapy using BMP has been attempted (Molecular Medicine, 37, 709 (2000)). However, the mechanisms of action of BMP in these diseases have not been analyzed in detail, although a solution is desired.
BMP has been found to induce differentiation from a fibroblast to an osteoblast via the receptor, by using an alkaline phosphatase activity as an indicator (Biochemical and Biophysical Research Communications, 172, 295 (1990)). Further, it has been found that the activity of BMP is suppressed by chordin, a protein secreted by Spemann organizer tissue (Nature, 382, 595 (1996)) and that chordin does not bind to the BMP receptor, but directly binds to BMP and acts as an antagonist (Cell, 86, 589 (1996)). Recently, chordin has been determined to have four repeated structures (CR1 to CR4) which have a signal peptide at the amino terminal end and contain an abundance of Cysteine and bind to BMP via the characteristic structure (motif) (Development, 127, 821 (2000)). And, Kielin has been reported to be a secreted protein having a high homology with chordin (Proceedings of the National Academy of Sciences, 97(10), 5291-5296 (2000)). At present, chordin-like proteins other than Kielin are suggested to exist. But, the reality is not clear and the discovery of novel proteins has been sought for the analysis of the mechanism of action of BMP.
On the other hand, cancer may be present in most tissues of the body. Many oncogenes, cancer target genes, and anti-oncogenes have been discovered, and mechanisms of human carcinogenesis are continuing to being discovered on a specified gene level. However, mechanisms of carcinogenesis have not been completely clarified. There is a possibility of unknown genes being involved therein. For example, causative genes have not yet been identified in parotid cancer, esophagus cancer, duodenal carcinoma, ureteral cancer, testicle cancer, ovarian cancer, uterine cancer, intestinal cancer, rectal cancer, biliary cancer and thyroid cancer. An identification of novel genes concerning pathogenesis of cancer and diagnostic methods using the gene have been desired for these diseases. Since cancer cells commonly proliferate in a dedifferentiated state, there are many trials that use factors and pharmaceutical compositions for modulating differentiation of carcinoma cells as anticancer agents. However, such trials can not suppress all cancers. Thus, novel factors and pharmaceutical compositions possessing activity of modulating differentiation are desired.